Many cancer drugs exhibit low solubility in aqueous solution and lack tissue specificity. This necessitates the use of carrier formulations to increase availability and reduce side effects. Nanometer-sized therapeutic delivery agents are an ideal choice because they exhibit enhanced blood circulation times and accumulate preferentially in tumors. One objective of this research is to develop a high capacity hydrophobic drug carrier by attaching synthetic polymer chains to the interior of a naturally occurring nanocapsule called a vault. A second objective is to develop a vault-polymer conjugate displaying an antibody to a breast cancer cell surface receptor to enhance targeting to the cell. Two specific aims are proposed to reach these objectives. The first aim is to determine drug loading and release from protein vaults modified in the interior with hydrophobic polymers. It is hypothesized that vaults modified at the interior with hydrophobic polymers will incorporate hydrophobic drugs. To accomplish this, hydrophobic polymer-vault conjugates will be synthesized by polymerizing from initiation sites on the interior of the vaults. Drug incorporation and release kinetics will be quantified. The second aim is to investigate cellular binding, uptake and in vitro cytotoxic effect of cancer drug-loaded vaults in breast cancer cell culture. It is hypothesized that vault- polymer drug loaded conjugates modified at the exterior with targeting ligands will reduce breast cancer cell viability. To investigate this, vault-polymer drug loaded conjugates modified on the exterior with receptor targeting ligands will be incubated in culture with breast cancer cells and inhibition of cell viability will be quantified. Results will be compared to that of empty vaults and to currently available formulation technology. One potential outcome of this research is the development of a new nanocapsule for delivery of hydrophobic cancer drugs. Specifically, delivery of an important therapeutic, paclitaxel, to breast cancer cells will be investigated. Thus, this work is expected to be directly relevant to breast cancer therapy. The long term goal of this research is to create a general modular nanocapsule to deliver hydrophobic drugs to treat a variety of diseases. PUBLIC HEALTH RELEVANCE: Vault-polymer nanocapsules that sequester and deliver hydrophobic drugs to targeted cells can lead to multifunctional therapeutic delivery agents to treat cancer.